RNA-seq of murine tibialis anterior muscle treated with AAV expressing AR isoform 2 (AR45) or AAV-GFP
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE166655 | GEO | 2021/06/29
REPOSITORIES: GEO
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Project description:RNA-seq of murine tibialis anterior muscle treated with AAV expressing AR isoform 2 (AR45) or AAV-GFP
| PRJNA701490 | ENA
Project description:Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor (AR). Previous studies have shown that transcriptional dysregulation and mitochondrial impairment occur in SBMA. We used gene-expression analysis and ChIP-sequencing to map transcriptional changes in SBMA induced pluripotent stem cell-derived motor neurons. The SBMA cells had decreased expression of genes encoding electron transport chain subunits and other metabolic proteins, associated with reduced histone acetylation which may be contributing to mitochondrial dysfunction. AR ChIP-sequencing results indicate that this is not a direct transcriptional effect of mutant AR on mitochondrial gene expression. Furthermore, we found decreased acetyl-CoA, and pyruvate supplementation to correct this deficiency improved mitochondrial function and SBMA motor neuron viability. We propose that epigenetic dysregulation of metabolic genes contributes to reduced mitochondrial ATP production. Our results show a molecular link between altered epigenetic regulation and mitochondrial metabolism that contributes to neurodegeneration.
2020-08-10 | GSE140017 | GEO
Project description:The pattern of gene expression changes was analyzed in the skeletal muscle of transgenic mouse models of Spinal and bulbar muscular atrophy (SBMA) at 1 and 2 month of age.
2023-01-19 | GSE221480 | GEO
Project description:Together with the Estrogen, Progesterone, and Glucocorticoid Receptors, the Androgen Receptor (AR) is a member of the type I nuclear receptor superfamily, a class of transcription factors that are activated by steroid hormones1. Nuclear receptors share a common three-domain structure, comprising a highly variable amino-terminal domain (NTD), with potent transcriptional activator capability, a central two zinc finger motifs DNA-binding domain (DBD), and a well-conserved carboxy-terminal ligand-binding domain (LBD) responsible for interacting with the transcriptional machinery1. Given their modular structure, expression of isoforms resulting from alternative splicing or starting and termination events have profound effects on nuclear receptor activity and function. Several AR variants (AR-Vs) have been identified from prostate cancer clinical specimens, arising from multiple mechanisms, including genomic rearrangements2 and upregulation of splicing factors3. This seminal discovery has provided the molecular basis for a deeper understanding of AR-related diseases, with potential to be translated in identification of novel therapeutic targets and promising prognostic markers4–6. By deeply sequencing the transcriptome of human brains, here we identified AR-2 as the most expressed AR isoform. Furthermore, we found that AR-2 is widely expressed in other human tissues, forms heterodimers with the full length AR and acts as a repressor of its transcriptional activity. Delivery of this isoform via adeno-associated virus (AAV9) resulted in significant amelioration of the disease phenotype in a mouse model of spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease with unmet clinical need caused by a toxic gain of function of polyglutamine-expanded (polyQ) AR7. Collectively, these results establish a physiological role of AR-2 in fine-tuning full length AR activity and demonstrate the feasibility and therapeutic benefit of modulating this variant for treating SBMA and other AR-related diseases.
2021-06-29 | GSE138053 | GEO
Project description:Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s Disease, is a slowly progressive adult-onset neuromuscular disease which results from a polyglutamine (polyQ) encoding CAG repeat expansion within the androgen receptor gene (AR). Despite the ubiquitous expression of the androgen receptor, it is unclear why motor neurons selectively degenerate and there are no effective treatments or disease modifying therapies for this debilitating disease. In order to identify potential therapeutic targets, we set out to establish the genes and molecular pathways involved in early motor neuron dysfunction in SBMA. We therefore undertook global transcriptomic profiling of cultured primary embryonic motor neurons from the spinal cord of AR100 mice, which model SBMA.. Four biological replicate samples were used for genome wide analysis using Affymetrix 430 v2.0 mouse arrays. Data was normalised using therobust multichip average (RMA) algorithm.
2019-05-02 | E-MTAB-6986 | biostudies-arrayexpress
Project description:RNA sequence was performed using mRNAs of motor neurons derived from iPSCs of four patients of spinal bulbar muscular atrophy (SBMA) and four age- and sex- matched controls. The analysis was performed using purified motor neurons by flowcytometry and cell sorting based on the expression of HB9e438::Venus reporter gene (P4) or unpurified motor neurons (NT).
2020-03-02 | GSE142612 | GEO
Project description:Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor (AR). Previous studies have shown that transcriptional dysregulation and mitochondrial impairment occur in SBMA. We used gene-expression analysis and ChIP-sequencing to map transcriptional changes in SBMA induced pluripotent stem cell-derived motor neurons. The SBMA cells had decreased expression of genes encoding electron transport chain subunits and other metabolic proteins, associated with reduced histone acetylation which may be contributing to mitochondrial dysfunction. AR ChIP-sequencing results indicate that this is not a direct transcriptional effect of mutant AR on mitochondrial gene expression. Furthermore, we found decreased acetyl-CoA, and pyruvate supplementation to correct this deficiency improved mitochondrial function and SBMA motor neuron viability. We propose that epigenetic dysregulation of metabolic genes contributes to reduced mitochondrial ATP production. Our results show a molecular link between altered epigenetic regulation and mitochondrial metabolism that contributes to neurodegeneration.
2020-08-10 | GSE140016 | GEO
Project description:Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor (AR). Previous studies have shown that transcriptional dysregulation and mitochondrial impairment occur in SBMA. We used gene-expression analysis and ChIP-sequencing to map transcriptional changes in SBMA induced pluripotent stem cell-derived motor neurons. The SBMA cells had decreased expression of genes encoding electron transport chain subunits and other metabolic proteins, associated with reduced histone acetylation which may be contributing to mitochondrial dysfunction. AR ChIP-sequencing results indicate that this is not a direct transcriptional effect of mutant AR on mitochondrial gene expression. Furthermore, we found decreased acetyl-CoA, and pyruvate supplementation to correct this deficiency improved mitochondrial function and SBMA motor neuron viability. We propose that epigenetic dysregulation of metabolic genes contributes to reduced mitochondrial ATP production. Our results show a molecular link between altered epigenetic regulation and mitochondrial metabolism that contributes to neurodegeneration.
2020-08-10 | GSE140015 | GEO
Project description:Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by short GCN repeat expansions within the gene encoding the nuclear poly(A)-binding protein 1 (PABPN1) that extend an N-terminal polyalanine tract in the protein. Mutant PABPN1 aggregates as nuclear inclusions in OMPD patient muscles. We have used the transgenic mouse A17.1 OPMD model that recapitulates the features of the human disorder: progressive muscle weakness, atrophy and formation of PABPN1 nuclear inclusions. Wild-type human PABPN1 contains a stretch of 10 alanines following the initial methionine, which is expanded to 11–18 alanines in OPMD patients. Transgenic A17.1 mouse overexpress an 17 alanine expanded PABPN1 under the control of the HSA promoter. To evaluate a gene therapy approach based on AAV delivery of a ‘suppress and replace’ strategy in OPMD we performed a transcriptomic analysis in treated muscles 18 weeks after injection. Using microarrays, tibialis anterior gene expression was compared between control muscles (FvB), OPMD muscles (A17), AAV-shRNA3x treated muscles (A17 shRNA3X), AAVoptPABPN1 treated muscles (A17 optPABPN1), and AAV-shRNA3x+AAV-optPABPN1 treated muscles (A17 dual).
2017-06-12 | GSE89996 | GEO
Project description:Duchenne muscular dystrophy (DMD) is characterized by impaired cytoskeleton organization, cytosolic calcium handling oxidative stress and mitochondrial dysfunction. This results in progressive and fatal muscle damage, wasting and weakness. The Striated Muscle activator of Rho signalling (STARS) is an actin binding protein that activates the myocardin-related transcription factor-A (MRTFA)/serum response factor (SRF) transcriptional pathway; a pathway that regulates cytoskeletal structure, muscle function, growth and repair. Here we investigated the regulation of several members of the STARS signalling pathway in muscle from patients with DMD and the dystrophin-deficient mdx and dko (utrophin‐ and dystrophin‐null) mice. A reduction in protein levels of STARS, SRF and RHOA, and an increase in MRTFA were observed in quadriceps muscle of patients with DMD. STARS, SRF and MRTFA mRNA levels were also decreased in DMD muscle, while Stars mRNA levels were decreased in mdx tibialis anterior (TA) muscle and Srf and Mrtfa mRNAs were decreased in dko TA muscle. Overexpressing the human STARS (hSTARS) protein in mdx TA muscle increased maximal isometric specific force by 13%. This was not associated with changes in muscle mass, fibre cross-sectional area (CSA), fibre type, centralized nuclei or collagen deposition. Proteomics screening identified 31 upregulated and 22 downregulated proteins or individual peptides that were significantly regulated by hSTARS overexpression. Pathway enrichment analysis indicated that hSTARS overexpression regulated the keratin, NRF2 and oxidative phosphorylation (OXPHOS) pathways. These pathways are impaired in dystrophic muscle and regulate cytoskeleton organization, oxidative stress and mitochondrial energy production; processes that are vital for muscle function. We conclude that increasing the STARS protein in dystrophic muscle improves muscle force production, potentially via its regulation of multiple pathways that positively influence cytoskeletal structure, oxidative stress and energy production.
2021-08-12 | PXD024631 | Pride